Adult bone marrow-derived stem cells use R-cadherin to target sites of neovascularization in the developing retina.

Adult bone marrow contains a population of hematopoietic stem cells (HSCs) that can give rise to cells capable of targeting sites of neovascularization in the peripheral or retinal vasculature. However, relatively little is known about the mechanism of targeting of these cells to sites of neovascularization. We have analyzed subpopulations of HSCs for the expression of a variety of cell surface adhesion molecules and found that R-cadherin, a calcium-dependent cell-cell adhesion molecule important for normal retinal endothelial cell guidance, was preferentially expressed by functionally targeting HSCs. Preincubation of HSCs with function-blocking anti-R-cadherin antibodies or novel R-cadherin-specific peptide antagonists effectively prevented targeting of bone marrow-derived cells to the developing retinal vasculature in vivo. Whereas control-injected HSCs targeted to all 3 normal developing retinal vascular layers, blocking R-cadherin-mediated adhesion resulted in mistargeting of the HSCs to the normally avascular outer retina. Our results suggest that vascular targeting of bone marrow-derived HSCs is dependent on mechanisms similar to those used by endogenous retinal vascular endothelial cells. Thus, R-cadherin antagonists may be useful in the treatment of neovascular diseases in which circulating HSCs contribute to abnormal angiogenesis.     

Evaluating Factors Contributing to Dropout in a Large Peritoneal Dialysis Program

BackgroundThe low prevalence of peritoneal dialysis (PD) (9%) vs. hemodialysis (HD) (88.2%) is partly due to patient dropout from therapy.MethodsThis retrospective study identified patients who withdrew from PD between 2016 and 2018 in our program. We evaluated all other factors as controllable losses. Analysis included time on therapy at dropout (very early, early or late) and method of initiation (HD to PD conversion, unplanned PD, or planned start).ResultsEighty-three patients enrolled into our PD program. 27 dropped out; 24 were due to controllable factors, 3 due to death, with a median age at dropout of 52 years old. We determined psychosocial factors (PF) to be the largest controllable factor influencing dropout; contributing a 63% rate among all controllable factors. When considering time until dropout, 100% of very early dropout patients and 50% of late dropout patients did so due to PF. Among early dropout patients 67% dropped out due to other medical reasons. The mean time to dropout for PF, other, and infection (INF) were 13, 26, and 33 months, respectively. When considering type of initiation, we found PF to be the largest attributable factor with 50% of unplanned, 100% of planned, and 50% of conversions stopping therapy.ConclusionsOur study indicates that the primary reason for controllable loss from therapy was secondary to PF regardless of the time on therapy or the method of initiation to therapy.     

Increasing Endocannabinoid Levels in the Ventral Pallidum Restore Aberrant Dopamine Neuron Activity in the Subchronic PCP Rodent Model of Schizophrenia

Background:

Schizophrenia is a debilitating disorder that affects 1% of the US population. While the exogenous administration of cannabinoids such as tetrahydrocannabinol is reported to exacerbate psychosis in schizophrenia patients, augmenting the levels of endogenous cannabinoids has gained attention as a possible alternative therapy to schizophrenia due to clinical and preclinical observations. Thus, patients with schizophrenia demonstrate an inverse relationship between psychotic symptoms and levels of the endocannabinoid anandamide. In addition, increasing endocannabinoid levels (by blockade of enzymatic degradation) has been reported to attenuate social withdrawal in a preclinical model of schizophrenia. Here we examine the effects of increasing endogenous cannabinoids on dopamine neuron activity in the sub-chronic phencyclidine (PCP) model. Aberrant dopamine system function is thought to underlie the positive symptoms of schizophrenia.

Methods:

Using in vivo extracellular recordings in chloral hydrate–anesthetized rats, we now demonstrate an increase in dopamine neuron population activity in PCP-treated rats.

Results:

Interestingly, endocannabinoid upregulation, induced by URB-597, was able to normalize this aberrant dopamine neuron activity. Furthermore, we provide evidence that the ventral pallidum is the site where URB-597 acts to restore ventral tegmental area activity.

Conclusions:

Taken together, we provide preclinical evidence that augmenting endogenous cannabinoids may be an effective therapy for schizophrenia, acting in part to restore ventral pallidal activity.     

Induction and treatment of anergy in murine leprosy

Leprosy is a disease consisting of a spectrum of clinical, bacteriological, histopathological and immunological manifestations. Tuberculoid leprosy is frequently recognized as the benign polar form of the disease, while lepromatous leprosy is regarded as the malignant form. The different forms of leprosy depend on the genetic and immunological characteristics of the patient and on the characteristics of the leprosy bacillus. The malignant manifestations of lepromatous leprosy result from the mycobacterial‐specific anergy that develops in this form of the disease. Using murine leprosy as a model of anergy in this study, we first induced the development of anergy to Mycobacterium lepraemurium (MLM) in mice and then attempted to reverse it by the administration of dialysable leucocyte extracts (DLE) prepared from healthy (HLT), BCG‐inoculated and MLM‐inoculated mice. Mice inoculated with either MLM or BCG developed a robust cell‐mediated immune response (CMI) that was temporary in the MLM‐inoculated group and long‐lasting in the BCG‐inoculated group. DLE were prepared from the spleens of MLM‐ and BCG‐inoculated mice at the peak of CMI. Independent MLM intradermally‐inoculated groups were treated every other day with HLT‐DLE, BCG‐DLE or MLM‐DLE, and the effect was documented for 98 days. DLE administered at a dose of 1.0 U (1 × 10⁶ splenocytes) did not affect the evolution of leprosy, while DLE given at a dose of 0.1 U showed beneficial effects regardless of the DLE source. The dose but not the specificity of DLE was the determining factor for reversing anergy.     

T-level downstaging and complete pathologic response after preoperative chemoradiation for advanced rectal cancer result in decreased recurrence and improved disease-free survival

PURPOSE: Preoperative chemoradiation therapy is used widely in the treatment of rectal cancer. The predictive value of response to neoadjuvant remains uncertain. We retrospectively evaluated the impact of response to preoperative and, specifically, of T-level downstaging, nodal downstaging, and complete pathologic response after chemoradiation therapy on oncologic outcome of patients with locally advanced rectal cancer. METHODS: There were 88 patients with ultrasound Stage T3/T4 midrectal (n = 37) and low rectal (n = 51) cancers (63 males; mean age 62.6 years). All patients were treated by preoperative 5-fluorouracil-based chemotherapy and pelvic radiation followed by surgical resection in six weeks or longer (56 sphincter-preserving resections). RESULTS: T-level downstaging after neoadjuvant treatment was demonstrated in 36 (41 percent) of 88 patients, and complete pathologic response was observed in 16 (18 percent) of the 88. Of the 42 patients with ultrasound-positive nodes, 27 had no evidence of nodal involvement on pathologic evaluation (64 percent). The overall response rate (T-level downstaging or nodal downstaging) was 51 percent. At a median follow-up of 33 months, 86.4 percent of patients were alive. The overall recurrence rate was 10.2 percent (three patients had local and six had metastatic recurrences). Patients with T-level downstaging and complete pathologic response were characterized by significantly better disease-free survival (P = 0.03, P = 0.04) and better overall survival (P = 0.07, P = 0.08), according to Wilcoxons test comparing Kaplan-Meier survival curves. None of the patients with complete pathologic response developed recurrence or died during the follow-up period. CONCLUSION: T-level downstaging and complete pathologic response after preoperative chemoradiation therapy followed by definitive surgical resection for advanced rectal cancer resulted in decreased recurrence and improved disease-free survival. Advanced rectal cancers that undergo T-level downstaging and complete pathologic response after chemoradiation therapy may represent subgroups that are characterized by better biologic behavior.     

One Egg per Day Improves Inflammation when Compared to an Oatmeal-Based Breakfast without Increasing Other Cardiometabolic Risk Factors in Diabetic Patients

There is concern that egg intake may increase blood glucose in patients with type 2 diabetes mellitus (T2DM). However, we have previously shown that eggs reduce inflammation in patients at risk for T2DM, including obese subjects and those with metabolic syndrome. Thus, we hypothesized that egg intake would not alter plasma glucose in T2DM patients when compared to oatmeal intake. Our primary endpoints for this clinical intervention were plasma glucose and the inflammatory markers tumor necrosis factor (TNF)-α and interleukin 6 (IL-6). As secondary endpoints, we evaluated additional parameters of glucose metabolism, dyslipidemias, oxidative stress and inflammation. Twenty-nine subjects, 35–65 years with glycosylated hemoglobin (HbA1c) values <9% were recruited and randomly allocated to consume isocaloric breakfasts containing either one egg/day or 40 g of oatmeal with 472 mL of lactose-free milk/day for five weeks. Following a three-week washout period, subjects were assigned to the alternate breakfast. At the end of each period, we measured all primary and secondary endpoints. Subjects completed four-day dietary recalls and one exercise questionnaire for each breakfast period. There were no significant differences in plasma glucose, our primary endpoint, plasma lipids, lipoprotein size or subfraction concentrations, insulin, HbA1c, apolipoprotein B, oxidized LDL or C-reactive protein. However, after adjusting for gender, age and body mass index, aspartate amino-transferase (AST) (p < 0.05) and tumor necrosis factor (TNF)-α (p < 0.01), one of our primary endpoints were significantly reduced during the egg period. These results suggest that compared to an oatmeal-based breakfast, eggs do not have any detrimental effects on lipoprotein or glucose metabolism in T2DM. In contrast, eggs reduce AST and TNF-α in this population characterized by chronic low-grade inflammation.     

Latest culture techniques: cracking the secrets of bone marrow to mass-produce erythrocytes and platelets ex vivo

Since the dawn of medicine, scientists have carefully observed, modeled and interpreted the human body to improve healthcare. At the beginning there were drawings and paintings, now there is three-dimensional modeling. Moving from two-dimensional cultures and towards complex and relevant biomaterials, tissue-engineering approaches have been developed in order to create three-dimensional functional mimics of native organs. The bone marrow represents a challenging organ to reproduce because of its structure and composition that confer it unique biochemical and mechanical features to control hematopoiesis. Reproducing the human bone marrow niche is instrumental to answer the growing demand for human erythrocytes and platelets for fundamental studies and clinical applications in transfusion medicine. In this review, we discuss the latest culture techniques and technological approaches to obtain functional platelets and erythrocytes ex vivo. This is a rapidly evolving field that will define the future of targeted therapies for thrombocytopenia and anemia, but also a long-term promise for new approaches to the understanding and cure of hematologic diseases.     

The appropriateness of use of percutaneous transluminal coronary angioplasty in Spain

BACKGROUND: The rapid increase in the number of percutaneous transluminal coronary angioplasty (PTCA) procedures performed in Spain in recent years raises questions about how appropriately this procedure is being used. To examine this issue, we studied the appropriateness of use of PTCA in Spanish patients and factors associated with inappropriate use. METHODS: We applied criteria for the appropriate use of PTCA developed by an expert panel of Spanish cardiologists and cardiovascular surgeons to a random sample of 1913 patients undergoing PTCA in Spain in 1997. The patients were selected through a two-step sampling process, stratifying by hospital type (public/private) and volume of procedures (low/medium/high). We examined the association between inappropriate use of PTCA and different clinical and sociodemographic factors. RESULTS: Overall, 46% of the PTCA procedures were appropriate, 31% were uncertain and 22% were inappropriate. Two factors contributing to inappropriate use were patients' receipt of less than optimal medical therapy and their failure to undergo stress testing. Institutional type and volume of procedures were not significantly related with inappropriate use. CONCLUSIONS: One of every five PTCA procedures in Spain is done for inappropriate reasons. Assuring that patients receive optimal medical therapy and undergo stress testing when indicated could contribute to more appropriate use of PTCA.